Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality studyCommentary: Role of other genes and environment should not be overlooked in monogenic disease

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Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality studyCommentary: Role of other genes and environment should not be overlooked in monogenic disease

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Most patients presented with rather progressive weakness or loss of
co-ordination in the lower limbs. Neuropathy - and its association with
statins - was discovered by nerve conduction studies. In some cases, it is
the patient who first suspected the association. Weakness occured within
two months of instituting, or increasing dosage, of the statin. The
neuropathy is severe and in several cases leading to muscle denervation.
Neuropathy may reverse if the stain is stopped. Yet neuropathy was not
suspected and the patient asked to continue on the statin.

EDITOR - The study by Sijbrands and colleagues is a valuable
contribution to our understanding of the natural history and clinical
significance of Familial Hypercholesterolaemia (FH).1

Studies on FH are susceptible biase as the families are almost
invariably identified when members present with coronary heart disease
(CHD). The findings of the First and Second European Atherosclerosis
Research Studies (EARS I and II) indicate that FH is not a significant
factor in premature CHD. The EARS studies were established to investigate
the importance and interaction of genetic and environmental factors in the
development of atherosclerosis.2

In the EARS studies, University students between the ages of 18 and
26 years, whose fathers had proven CHD before the age of 55 years, were
recruited from the local indigenous population attending 18 Universities
throughout Europe. Age and sex-matched controls were recruited from the
same populations for each case. Applying the Simon Broome Foundation
criteria for the diagnosis of possible FH, ie a cholesterol >7.5
mmol/l,3 only 2 of 1089 students with a proven family history of paternal
premature CHD and 4 of 1727 controls had FH. Thus, the prevalence of FH
in both groups was not significantly different at approximately 1 in 500,
which is the estimated prevalence of the condition in the general
population.

While it has been proven beyond reasonable doubt that hyperlipidaemia
is a major risk factor for atherosclerosis and that reducing plasma lipid
concentrations by lifestyle or drug treatment will delay or even reverse
the development of atherosclerosis, the evidence that heterozygote FH is,
of itself, a cause of atherosclerosis is unsatisfactory.

The mortality from this study follows exactly the dramatic rise and
fall of heart disease in the previous century. (1) It is of course clear
that ‘cholesterol’ is unable to explain the epidemic pattern, since the
rise was unparalleled by increases in fat consumption necessary to affect
it. ( the increases would have to be truly enormous).

Besides, to think that Cholesterol, an essential substance in our
lives, suddenly, in the previous century should have become toxic, is
nonsense. Such a hypothesis that the rise in heart disease should have
been caused by increased fat consumption is crucified on the cross of
biology. Our blood cholesterol is well protected by feedback mechanisms.
Only truly momentous changes would affect it as every physician can
observe every day in his own patients.

And the fall in heart disease goes on just as it has for the last 35
years completely, it seems, unaware of the ‘scientifically proven’ fact
that cholesterol is a killer.(2)

The findings by Sijbrands et al1 that unselected individuals from a
pedigree with familial hypercholesterolemia had a normal life span and a
standard mortality close to one is further evidence that the LDL-
hypothesis, the foundation of the cholesterol campaign, is wrong. Patients
with familial hypercholesterolaemia usually have a total serum cholesterol
around ten or even higher. Extrapolating from the data of the MR.FIT
screenees2 a cholesterol value of that level is associated with a risk of
coronary death that is at least ten times higher than in individuals with
a low to normal cholesterol. The low standard mortality seen in the Dutch
pedigree of individuals with familial hypercholesterolaemia is therefore
best explained by a protective effect of a high cholesterol in this
condition, for instance against infections, as suggested by the authors.

This explanation is in accord with the idea that atherosclerosis has an
infectious origin, but also with the fact that in many studies a high
cholesterol in old people was associated with a low risk of coronary and
total mortality.

Why then is a high cholesterol a risk factor for coronary heart disease in
individuals without familial hypercholesterolaemia? And why does coronary
heart disease occur at a very young age in some individuals affected with
this disease? In the first group the high cholesterol may be secondary to
other, more important factors, such as lack of exercise, mental stress,
smoking, and overweight, all of which are known to be associated with an
elevated cholesterol.3 In the second, the deposition of cholesterol in the
artery walls may, by genetic or environmental reasons,1 be more pronounced
in some pedigrees.

That a high cholesterol is a secondary phenomenon and not the very cause
of atherosclerosis is in accord with other observations. For instance,
there is no correlation between the serum cholesterol concentration and
the degree of atherosclerosis seen at autopsy;3 there is no association
between spontaneous or induced variations in the serum cholesterol
concentration and atherosclerosis growth at angiography;3 a lowering of
cholesterol by diet or non-statin drugs does not affect coronary or total
mortality;3 and the protective effect of the statins is independent on the
degree of cholesterol lowering, indicating that the statins exert their
effect by other ways than by a lowering of the cholesterol concentration.3
It is time for a paradigm shift in atherosclerosis research.